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Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds |
| 7560466 |
Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
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| Patent Drawings: | |
| Inventor: |
Singh, et al. |
| Date Issued: |
July 14, 2009 |
| Application: |
11/539,520 |
| Filed: |
October 6, 2006 |
| Inventors: |
Singh; Rajinder (Belmont, CA)
Argade; Ankush (Foster City, CA)
Li; Hui (Santa Clara, CA)
Bhamidipati; Somasekhar (Foster City, CA)
Carroll; David (San Francisco, CA)
Sylvain; Catherine (San Mateo, CA)
Clough; Jeffrey (Redwood City, CA)
Keim; Holger (Wyckoff, NJ)
|
| Assignee: |
Rigel Pharmaceuticals, Inc. (South San Francisco, CA) |
| Primary Examiner: |
Balasubramanian; Venkataraman |
| Assistant Examiner: |
|
| Attorney Or Agent: |
McDonnell Boehnen Hulbert & Berghoff LLP |
| U.S. Class: |
514/272; 514/224.2; 514/230.5; 514/274; 514/275; 544/105; 544/320; 544/323; 544/324; 544/51; 544/52 |
| Field Of Search: |
544/320; 544/323; 544/324; 544/51; 544/52; 544/105; 514/275; 514/272; 514/224.2; 514/230.5 |
| International Class: |
C07D 403/12; C07D 405/12; C07D 409/12; C07D 411/12; C07D 413/12; C07D 417/12; A61K 31/4353; A61K 31/506; A61K 31/5377; A61K 31/541; A61P 19/02; A61P 35/00; A61P 37/00 |
| U.S Patent Documents: |
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| Foreign Patent Documents: |
748087; 2542492; 4029650; 0 139 613; 0 248 348; 0 432 893; 0 525 768; 1 056 742; 1 598 343; 2373186; 03/127790; 1499883; WO 90/12790; WO 91/18887; WO 95/19358; WO 97/19065; WO 98/41512; WO 99/24874; WO 99/31073; WO 99/33846; WO 99/41253; WO 99/50249; WO 99/50250; WO 99/50251; WO 99/61437; WO 00/12485; WO 00/27825; WO 00/27826; WO 00/33844; WO 00/39101; WO 00/56714; WO 00/58305; WO 00/59892; WO 00/59893; WO 00/63182; WO 00/76980; WO 00/78731; WO 01/00213; WO 01/09134; WO 01/19825; WO 01/22938; WO 01/23362; WO 01/23389; WO 01/29009; WO 01/30782; WO 01/47897; WO 01/60816; WO 01/64654; WO 01/64655; WO 01/64656; WO 01/72744; WO 01/85699; WO 01/85700; WO 02/04429; WO 02/16306; WO 02/22601; WO 02/45652; WO 02/47690; WO 02/50066; WO 02/059110; WO 02/059112; WO 02/062789; WO 02/064096; WO 02/066461; WO 02/066480; WO 02/066481; WO 02/068409; WO 02/096888; WO 02/102313; WO 03/000186; WO 03/002542; WO 03/002544; WO 03/016306; WO 03/018021; WO 03/018022; WO 03/026664; WO 03/026665; WO 03/026666; WO 03/030909; WO 03/032994; WO 03/032997; WO 03/040141; WO 03/045923; WO 03/048133; WO 03/055489; WO 03/062225; WO 03/063794; WO 03/066601; WO 03/074515; WO 03/076437; WO 03/078404; WO 03/094920; WO 03/106416; WO 03/106451; WO 2004/002964; WO 2004/014382; WO 2004/014384; WO 2004/039359; WO 2004/041814; WO 2004/046118; WO 2004/048343; WO 2004/050068; WO 2004/054617; WO 2004/056786; WO 2004/067516; WO 2004/069812; WO 2004/074244; WO 2004/074261; WO 2004/074262; WO 2004/080980; WO 2005/007646; WO 2005/009978; WO 2005/009980; WO 2005/012294; WO 2005/013996; WO 2005/016893; WO 2005/016894; WO 2005/026130; WO 2005/026158; WO 2005/027848; WO 2005/037800; WO 2005/118544; WO 2006/034872; WO 2006/035068; WO 2006/074057; WO 2006/078846; WO 2006/133426; WO 2007/006926; WO 2007/027238; WO 2007/053452; WO 2007/072158; WO 2007/085540; WO 2007/085833; WO 2007/098507; WO 2008/079719; WO 2008/092049 |
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| Abstract: |
The present invention provides methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds, as well as methods of treating, preventing or ameliorating symptoms associated with such diseases. Specific examples of autoimmune diseases that can be treated or prevented with the compounds include rheumatoid arthritis and/or its associated symptoms, systemic lups erythematosis and/or its associated symptoms and multiple sclerosis and/or its associated symptoms. |
| Claim: |
What is claimed is:
1. A 2,4 pyrimidinediamine compound according to structure: ##STR00034## or a salt, and/or N-oxide thereof, wherein: X is selected from the group consisting of N and CH; Yis selected from the group consisting of O, S, SO, SO.sub.2, S(O)NR.sup.36, NH and NR.sup.35; Z is selected from the group consisting of O, S, SO, SO.sub.2, S(O)NR.sup.36, NH and NR.sup.35; R.sup.5 is fluoro; each R.sup.6 independently is selectedfrom the group consisting of hydrogen, --OR.sup.d, --SR.sup.d, (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, --NR.sup.cR.sup.c, halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, --CN, --NC, --OCN, --SCN, --NO, --NO.sub.2, --N.sub.3, --S(O)R.sup.d,--S(O).sub.2R.sup.d, --S(O).sub.2OR.sup.d, --S(O)NR.sup.cR.sup.c; --S(O).sub.2NR.sup.cR.sup.c, --OS(O)R.sup.d, --OS(O).sub.2R.sup.d, --OS(O).sub.2OR.sup.d, --OS(O)NR.sup.cR.sup.c, --OS(O).sub.2NR.sup.cR.sup.c, --C(O)R.sup.d, --C(O)OR.sup.d,--C(O)NR.sup.cR.sup.c, --C(NH)NR.sup.cR.sup.c, --OC(O)R.sup.d, --SC(O)R.sup.d, --OC(O)OR.sup.d, --SC(O)OR.sup.d, --OC(O)NR.sup.cR.sup.c, --SC(O)NR.sup.cR.sup.c, --OC(NH)NR.sup.cR.sup.c, --SC(NH)NR.sup.cR.sup.c, --[NHC(O)].sub.nR.sup.d,--[NHC(O)].sub.nOR.sup.d, --[NHC(O)].sub.nNR.sup.cR.sup.c and --[NHC(NH)].sub.nNR.sup.cR.sup.c, (C5-C10) aryl optionally substituted with one or more of the same or different R.sup.8 groups, (C6-C16) arylalkyl optionally substituted with one or more ofthe same or different R.sup.8 groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R.sup.8 groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R.sup.8groups; R.sup.8 is selected from the group consisting of R.sup.e, R.sup.b, R.sup.e substituted with one or more of the same or different R.sup.a or R.sup.b, --OR.sup.a substituted with one or more of the same or different R.sup.a or R.sup.b,--B(OR.sup.a).sub.2, --B(NR.sup.cR.sup.c).sub.2, --(CH.sub.2).sub.mR.sup.b, --(CHR.sup.a).sub.mR.sup.b, --O--(CH.sub.2).sub.mR.sup.b, --S--(CH.sub.2).sub.m--R.sup.b, --O--CHR.sup.aR.sup.b, --O--CR.sup.a(R.sup.b).sub.2,--O--(CHR.sup.a).sub.m--R.sup.b,--O--(CH.sub.2).sub.m--CH[(CH.sub.2).sub.- mR.sup.b]R.sup.b, --S--(CHR.sup.a).sub.m--R.sup.b, --O--(CH.sub.2).sub.m--C(O)NH--(CH.sub.2).sub.mR.sup.b, --S--(CH.sub.2).sub.m--C(O)NH--(CH.sub.2).sub.m--R.sup.b,--O--(CHR.sup.a).sub.m--C(O)NH--(CHR.sup.a).sub.m--R.sup.b, --S--(CHR.sup.a).sub.m--C(O)NH--(CHR.sup.a).sub.m--R.sup.b, --NH--(CH.sub.2).sub.m--R.sup.b, --NH--(CHR.sup.a).sub.m--R.sup.b, --NH[(CH.sub.2).sub.mR.sup.b],--N[(CH.sub.2).sub.mR.sup.b].sub.2,--NH--C(O)--NH--CH.sub.2).sub.m--R.sup- .b, --NH--C(O)--(CH.sub.2).sub.m--CHR.sup.bR.sup.b and --NH--(CH.sub.2).sub.m--C(O)--NH--(CH.sub.2).sub.m--R.sup.b; each R.sup.a is independently selected from the groupconsisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16membered heteroarylalkyl; each R.sup.b is independently selected from the group consisting of .dbd.O, --OR.sup.d, (C1-C3) haloalkyloxy, .dbd.S, --SR.sup.d, .dbd.NR.sup.d, .dbd.NOR.sup.d, --NR.sup.cR.sup.c, halogen, --CF.sub.3, --CN, --NC, --OCN, --SCN,--NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, --S(O)R.sup.d, --S(O).sub.2R.sup.d, --S(O).sub.2OR.sup.d, --S(O)NR.sup.cR.sup.c, --S(O).sub.2NR.sup.cR.sup.c, --OS(O)R.sup.d, --OS(O).sub.2R.sup.d, --OS(O).sub.2OR.sup.d, --OS(O).sub.2NR.sup.cR.sup.c,--C(NH)NR.sup.cR.sup.c, --C(NR.sup.a)NR.sup.cR.sup.c, --C(NOH)R.sup.a, --C(NOH)NR.sup.cR.sup.c, --OC(O)R.sup.d, --OC(O)OR.sup.d, --OC(O)NR.sup.cR.sup.c, --OC(NH)NR.sup.cR.sup.c, --OC(NR.sup.a)NR.sup.cR.sup.c, [NHC(O)].sub.nR.sup.d,--[NR.sup.aC(O)].sub.nR.sup.d, --[NHC(O)].sub.nOR.sup.d, --[NR.sup.aC(O)].sub.nOR.sup.d--[NHC(O)].sub.nNR.sup.cR.sup.c, --[NR.sup.aC(O)].sub.nNR.sup.cR.sup.c, --[NHC(NH)].sub.nNR.sup.cR.sup.c and --[NR.sup.aC(NR.sup.a)].sub.nNR.sup.cR.sup.c; eachR.sup.c is independently a protecting group or R.sup.a, or, alternatively, two R.sup.c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more ofthe same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R.sup.a or R.sup.b groups; each R.sup.d is independently a protecting group or R.sup.a wherein protecting group is: an aminoprotecting group selected from the group consisting of formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl, substituted trityl, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl, and nitro-veratryloxycarbonyl; or a hydroxyl protecting group selected from the group consisting of benzyl ether, trityl ether, alkyl ether, tetrahydropyranyl ether, trialkylsilyl ether and allyl ether; each R.sup.e isindependently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10membered heteroaryl and 6-16 membered heteroarylalkyl; each R.sup.31, independently of the others, is (C1-C6) alkyl; each R.sup.35 is, independently of the others, selected from the group consisting of hydrogen and R.sup.8, or, alternatively, twoR.sup.35 bonded to the same carbon atom are taken together to form an oxo (.dbd.O), (.dbd.NH) or (.dbd.NR.sup.38) group; each R.sup.36 is independently selected from the group consisting of hydrogen and (C1-C6) alkyl; each R.sup.38 is selected from thegroup consisting of (C1-C6) alkyl and (C5-C14) aryl; each m is independently an integer from 1 to 3; and each n is independently an integer from 0 to 3.
2. The compound of claim 1 in which R.sup.6 is hydrogen.
3. The compound of claim 2 in which Y and Z are each, independently of one another, selected from the group consisting of O and NH.
4. The compound of claim 3 in which X is N.
5. The compound of claim 4 in which Y is O and Z is NH.
6. The compound of claim 5 in which two of R.sup.35 are (C1-C6) alkyl and two R.sup.35 bonded to the same carbon atom are taken together to form an oxo (.dbd.O).
7. A 2,4pyrimidinediamine compound according to structure: ##STR00035## or a salt, and/or N-oxide thereof, wherein: X is selected from the group consisting of N and CH; Y is selected from the group consisting of O, S, SO and SO.sub.2; Z isselected from the group consisting of NH and NR.sup.35; R.sup.5 is fluoro; each R.sup.31, independently of the others, is (C1-C6) alkyl; and each R.sup.35, independently of the others, is (C1- C6) alkyl.
8. The compound of claim 7 in which Y is O.
9. The compound of claim 8 in which Z is NH.
10. The compound of claim 9 in which X is N.
11. The compound of claim 9 in which X is CH. |
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